People with substance use disorders (SUD) have a high prevalence and rate of smoking with little success in quitting, so stronger approaches are needed to encourage attempts to quit smoking. Brief advice (BA), an approach designed to motivate cessation attempts, produced some benefit but low abstinence rates for smokers with SUDs while adding free transdermal nicotine replacement therapy (NRT) improved short-term rates. Varenicline, a partial agonist at a42 nicotinic acetylcholine receptors, has been found to produce higher rates of short and long-term abstinence for smokers in general than bupropion or placebo. However, a comparison between the efficacy of varenicline and NRT has not yet been published and no studies of varenicline have been conducted with people with SUDs. Given the lack of effectiveness for standard smoking treatments for this population, what needs to be known is whether varenicline would increase the smoking abstinence rates relative to NRT when all receive motivational counseling. The primary aim of this study is to evaluate the effects of 12 weeks of varenicline as compared to NRT, using a two-group randomized placebo-controlled design on smoking cessation rates for 12 months among 274 outpatients in treatment for SUD. The counseling incorporates BA (adapted slightly for sobriety settings by directly addressing barriers and concerns expressed by substance abusers), skills training and medication management. Confirmed point-prevalence and sustained abstinence will be assessed at 3, 6 and 12 months after the start of treatment. Secondary aims will examine potential mediators of effect including within treatment abstinence, craving, and nicotine withdrawal levels. The potential significance is to add to knowledge about the most effective ways to maximize smoking cessation among substance abusers, important given that no methods are known to work with this difficult population. No previous study has compared varenicline to NRT for efficacy nor investigated varenicline with patients with SUD.